Generation of Tr1 cells

Type I regulatory T (Tr1) cells are FoxP3- CD4+ T cells with strong immunosuppressive properties that were identified in various tissues during autoimmune inflammation. They are critical for the maintenance of tolerance, produce large amounts of IL-10, and have unique transcription factor requirements. Our laboratory was among the first to identify IL-27 as a differentiation factor for in vitro generation of Tr1 cells. We are currently applying cutting-edge methods to identify key steps in the differentiation of this novel T cell subset in order to harness their anti-inflammatory potential for the treatment of human autoimmune diseases.

Role of Tim-1 in immune responses

Tim-1 is a transmembrane glycoprotein identified as a member of the Tim family of genes that regulates immune responses. In the immune system, Tim-1 has been shown to be expressed on various immune cell populations. Currently, we are studying how Tim-1 regulates the development and function of regulatory B cells, in models of autoimmune disease.

Role of Tim-3 and other co-inhibitory receptors in T cell exhaustion and T cell inhibition

Co-inhibitory receptors, also called ‘check-point’ receptors, have received considerable attention as blockade of these receptors, such as PD-1 and CTLA-4, has proven to be an effective immunotherapeutic strategy against cancer. In chronic viral infections and cancer, the sustained expression of co-inhibitory receptors on CD8+ T cells is associated with dysfunctional or “exhausted” phenotype. Moreover, the accumulation of co-inhibitory-receptors on CD8 T cells correlates with increased dysfunction. Although co-inhibitory receptors clearly have a role in T cell dysfunction, how these co-inhibitory molecules are induced on effector T cells is not known. In addition to chronic viral infections and cancer, dysregulation of co-inhibitory pathways is also implicated in the pathogenesis of autoimmune diseases such as multiple sclerosis.


T cell immunoglobulin and mucin domain-containing 3 (Tim-3) was first identified in our laboratory and is a co-inhibitory receptor that is specifically expressed on differentiated interferon (IFNgamma)-producing CD4+ and CD8+ T cells, and induces their death and dysfunction. Recently, Tim-3 expression has been shown to mark the most severely “exhausted” or dysfunctional T cells that arise in chronic viral infections, such as HIV and HCV, as well as in cancer. Largely stemming from our work on Tim-3, agents that interfere with Tim-3 signaling are now in development for clinical trials in cancer. Currently, we are studying the pathways that drive expression of Tim-3 and the biochemical pathways by which Tim-3 mediates its effects in T cells.


T cell immunoreceptor with Immunoglobulin and ITIM domains (TIGIT) is a co-inhibitory receptor expressed on activated on CD4+, CD8+, and NK T cells, which binds to two ligands CD155 and CD112 expressed on antigen presenting cells. The laboratory has been working on the mechanisms by which TIGIT mediates inhibition of T cell responses. In addition to inducing IL-10+ DCs, we showed that TIGIT also has cell intrinsic inhibitory effects. TIGIT also directs the suppressor function of Foxp3+Tregs towards Th1 and Th17 cells but sparing Th2 cells from Treg mediated inhibition. Currently, we are investigating how the expression of each of these molecules is regulated and how they each achieve their inhibitory effects in T cells. We are further identifying new inhibitory receptors on T cells using systems biology approaches.

Th17 cells and induction of tissue inflammation

IL-17-producing Th17 cells are now considered to be the most potent effector T cell for inducing tissue inflammation in both experimental autoimmune disease models and in humans. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors on parenchymal tissues. Our laboratory was among the first to identify differentiation factors for Th17 cells. We showed that TGF-beta plus IL-6 or IL-21 together induces differentiation and amplification of Th17 differentiation but IL-23 stabilizes their development and evokes pathogenic phenotype in differentiating Th17 cells. By undertaking a high-density temporal transcriptomic analysis, in collaboration with the investigators at the Broad Institute, our laboratory was first to develop a regulatory network for the development of Th17 cells. Our laboratory also identified pathogenic and nonpathogenic Th17 cells that may have different functions in inducing inflammation vs. tissue homeostasis. Elucidation of the effects of these different Th17 cell subsets on disease is a major research effort in the laboratory.

Generation of TcR transgenic mice for myelin antigens

Autoimmune Disease Model: The laboratory has generated numerous models that recapitulate for the study of multiple sclerosis. The laboratory generated a TcR transgenic mouse that harbors reactivity to myelin proteolipid protein (PLP) and differentially develops disease on different genetic backgrounds. The 2D2 TcR transgenic mouse that harbors reactivity against myelin oligodendrocyte glycoprotein (MOG) is the “gold standard” in the field of CNS autoimmunity. The 1C6 TcR transgenic mouse is the only model that recapitulates the transition of relapsing-remitting disease to chronic progressive disease that is observed in MS patients. These models are widely used in the laboratory and in the field as tools to facilitate studies of immune mechanisms of autoimmune disease pathogenesis.

Generation of a novel model to study the role of Aquaporin-4 (AQP4) in Neuromyelitis optica (NMO)

Autoimmune Disease Model: Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system that is distinct from Multiple Sclerosis (MS) and is characterized by severe attacks of optic neuritis and myelitis in the spinal cord. The presence of serum autoantibody specific for the aquaporin-4 (AQP4) water channel is a powerful diagnostic marker for NMO. Thus, the role of APQ-4 autoantibodies in disease is an area of active research. AQP4-specific autoantibodies may play a pivotal role in the pathogenesis of NMO. However, immunization with AQP4 protein to induce NMO-like disease has met with limited success in recapitulating the disease in animal models. Since AQP4 is considered to be the primary autoantigen in NMO, this raises the important question whether AQP4-specific T cell: B cell collaboration would result in the development of NMO-like disease, and whether AQP4-specific B cells induce AQP4-specific T cells to differentiate into pathogenic effector T cells and drive development of NMO-like disease. To address these questions we are developing genetically engineered models harboring both antibodies and T cell receptors specific for AQP4 to understand their contribution to the pathogenesis of NMO. This project is supported in part by The Guthy-Jackson Charitable Foundation.